Clonal composition and persistence of antigen‐specific circulating T follicular helper cells

T follicular helper (T(FH)) cells play an essential role in promoting B cell responses and antibody affinity maturation in germinal centers (GC). A subset of memory CD4(+) T cells expressing the chemokine receptor CXCR5 has been described in human blood as phenotypically and clonally related to GC T(FH) cells. However, the antigen specificity and relationship of these circulating T(FH) (cT(FH)) cells with other memory CD4(+) T cells remain poorly defined. Combining antigenic stimulation and T cell receptor (TCR) Vβ sequencing, we found T cells specific to tetanus toxoid (TT), influenza vaccine (Flu), or Candida albicans (C.alb) in both cT(FH) and non‐cT(FH) subsets, although with different frequencies and effector functions. Interestingly, cT(FH) and non‐cT(FH) cells specific for C.alb or TT had a largely overlapping TCR Vβ repertoire while the repertoire of Flu‐specific cT(FH) and non‐cT(FH) cells was distinct. Furthermore, Flu‐specific but not C.alb‐specific PD‐1(+) cT(FH) cells had a “GC T(FH)‐like” phenotype, with overexpression of IL21, CXCL13, and BCL6. Longitudinal analysis of serial blood donations showed that Flu‐specific cT(FH) and non‐cT(FH) cells persisted as stable repertoires for years. Collectively, our study provides insights on the relationship of cT(FH) with non‐cT(FH) cells and on the heterogeneity and persistence of antigen‐specific human cT(FH) cells.